Neuroleptic dysphoria in animals.
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Animals↗
Biomedical subjects
G Bignami
Publications and source records attributed to G Bignami.
Interacting effects of oxazepam in late pregnancy and fostering procedure on mouse maternal behavior.
The present study was designed to assess the proactive effects of late pregnancy benzodiazepine (BDZ) treatment on maternal behavior in the postpartum period, using cross-fostering procedures to control for the role of changes produced prenatally in the offspring. Outbred CD-1 mouse dams were treated with either oxazepam (OX, 15 mg/kg PO twice/day on pregnancy days 12-16) or vehicle (VEH). After parturition, entire litters were exchanged either within treatments (in-fostered groups, IF) or between treatments (cross-fostered groups, CF), while additional litters were left undisturbed (un-fostered groups, UF). The behavior of lactating dams was observed in their home cages at 4, 8, and 12 days postpartum. Maternal responses, particularly nursing, were reduced in the OX-UF and OX-CF conditions and either normal or enhanced in the OX-IF condition. Correspondingly, locomotor/exploratory activity was markedly enhanced in the former conditions and close to the control level in the latter condition. In sum, the fostering variable appeared to determine whether pups raised by dams treated previously with BDZ receive either insufficient or exaggerated maternal care. This points to the need for a better understanding of mother/pup interactions in studies aimed at characterizing drug and toxicant effects on offspring development.
Animals↗
Pharmacology and anxiety: inadequacies of current experimental approaches and working models.
Current models concerning the mechanisms of punishment suppression and anxiolytic drug effects fail to account for several treatment-test interactions in pharmacological studies. This applies in the first place to some important "double dissociation" phenomena. For example, in rats benzodiazepines are effective in conflict tests (Geller- and Vogel-type) but not in go-no go avoidance discriminations, while the converse is true in the case of antimuscarinics. Such a situation makes it necessary to postulate a plurality of mechanisms which can serve punishment suppression in various conditions, and can operate at least partly "in parallel" rather than "in series". In addition, different varieties of a particular test can show quite different sensitivities to the same type of agent and/or different profiles in studies using various types of anxiolytics and antagonists. This does not preclude the use of one or the other test as a convenient assay. It appears, however, that we have only limited knowledge on the mechanisms involved in the production of behavioral effects which are assumed to be typical of the anxiolytic profile.
Animals↗
Ontogenetic and pharmacological dissociation of various components of locomotor activity and habituation in the rat.
Sprague-Dawley-derived male rats were used to investigate locomotor activity and habituation in an open field as a joint function of developmental age (2-6 weeks), pattern of test exposure (single 30-min test vs three 5-min tests at 24-hr intervals), and treatment conditions (i.p. saline, d-amphetamine sulfate 1 mg/kg, or scopolamine hydrocloride 0.5 mg/kg). No-drug animals showed low activity levels in both tests at the end of the second week, intermediate response rates at the end of the third week, and a typical adult-like pattern at later ages (high initial activity followed by marked within-session or between-session habituation). Amphetamine effects varied considerably depending jointly on age and type of test. At the end of the second week, the drug hyperactivity was much more marked in successive brief tests than in the single extended test. One week later, the response increase was rather uniform in both tests. At the end of the fourth week, the sensitivity profile was reversed, consisting of a large drug effect in the extended test but not in successive brief tests. Scopolamine was still without effects at this age, while a typical hyperactivity was produced by the drug in 6-week-old animals. These data show that, at least in the rat strain used, the functional maturation of muscarinic regulatory systems is not a necessary condition either for the appearance of an adult-like response pattern, or for the occurrence of the age- and test-related changes of the amphetamine profile.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Morphine effects on activity and pain reactivity of developing mice with or without late prenatal oxazepam exposure.
Locomotor activity in a Varimex apparatus, hot-plate responding, and morphine effects (1 and 10 mg/kg IP) were assessed in 14-, 21-, 28-, and 70-day old mice. The development of hot-plate responding consisted mainly of a progressive increase of latencies and a parallel reduction of sensitivity to morphine. Morphine depressed activity at 14 days at the lower dose, had no effect at 21 days, and produced an adult-like hyperactivity at 28 days (10 mg/kg). Prenatal oxazepam (15 mg/kg, given per os twice daily on days 12-16 of pregnancy) did not influence hot-plate responding and morphine analgesia at any of the test ages. By contrast, the data on activity, besides replicating the response reduction at 14 days observed previously in an open-field test (Alleva et al. 1985), showed a delayed appearance of morphine hyperactivity in oxazepam mice.
Aging↗
Avoidance methods in neurobehavioural toxicity assessments.
Avoidance methods have proven their usefulness at successive stages of toxicological investigation on a variety of different agents. First- and second-tier assessments can use simple versions of active and passive avoidance tests which are able to pick up a wide range of deficits at the sensory, motor, reinforcement, and associative level. Avoidance tests are also suitable for the study of tolerance, particularly if appropriate paradigms are used to separate contingent and noncontingent components of tolerance which can be produced by different mechanisms. In addition, these methods have been used successfully in many developmental studies with early (pre- or postnatal) treatment exposure. Higher-tier assessments aimed at a better definition of toxicity mechanisms are inevitably more complex, and can only be performed with agents of particular interest. Physiological psychologists and psychopharmacologists have evolved a considerable know-how in the combined use of selected types of avoidance in such assessments concerning lesion or drug syndromes. Relatively little of this know-how has been so far exploited in toxicological studies. However, some of the results obtained with toxicants which may selectively affect particular brain areas (e.g., limbic structures) appear to be quite promising. Overall, the results obtained by the use of avoidance methods concur with others in showing the close relation between the needs of toxicological assessments and the need for selective tools or probes in basic research on CNS mechanisms and behaviour.
Animals↗
Prenatal benzodiazepine effects in mice: postnatal behavioral development, response to drug challenges, and adult discrimination learning.
Oxazepam treatment of primiparous mouse dams on days 12-16 of pregnancy (15 mg/kg p.o. twice daily) produced a transient retardation of postnatal body growth and neurobehavioral development, a reduction of the hyperactivity response to amphetamine in open-field tests on postnatal days 14-16, and a selective impairment of adult active avoidance in four go-no go discrimination tasks. Equally important for understanding the nature of the prenatal benzodiazepine syndrome were several negative results, namely, the absence of changes in homing performance on postnatal day 10, an intact hyperactivity response to scopolamine on postnatal days 21-23, a lack of effects on adult activity, and a normal passive avoidance performance in the go-no go tasks. A modification in monoaminergic regulatory functions may account for the overall profile of prenatal drug effects. Based on the results of this experiment, of a preliminary multidose study (0-50 mg/kg), and of an additional cross-fostering experiment, several methodological issues are addressed. These include the choice of appropriate treatment schedules and of testing procedures adequate for each developmental stage, and the control for various confounding variables such as litter effects, postnatal maternal influences, and developmental history.
Amphetamine↗
[Experience of the researcher].
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Humans↗
Short-, medium-, and long-term effects of prenatal oxazepam on neurobehavioural development of mice.
A benzodiazepine (oxazepam) was given to nulliparous mice on days 12-16 of pregnancy, and the development and young adult behaviour of the offspring were studied. Experiment 1, using 5, 15, and 50 mg/kg doses given PO twice daily, showed a dose-dependent retardation of postnatal development of several responses such as righting, bar holding, limb placing, and auditory startle. These changes were maximal in the first 2 postnatal weeks and then were markedly attenuated, or disappeared, being apparently related to a temporary retardation of body growth. A reduction of locomotor activity at 60 days was found only in the 50 mg/kg group. The effects of the 15 mg/kg dose on postnatal body growth and neurobehavioural development were replicated in Experiments 2 and 3. Moreover, in these experiments prenatal oxazepam reduced open field activity at 14-16 days and attenuated the hyperactivity induced by dl-amphetamine sulphate (2 mg/kg IP). On the other hand activity, habituation, and response to a scopolamine challenge (2 mg/kg IP) at 21-23 days were not significantly different from those of appropriate controls. Experiment 3, using a cross-fostering procedure, showed that postnatal maternal effects were not responsible for the changes so far mentioned. Experiment 2 also investigated the acquisition of several go-no go avoidance discriminations in a shuttle-box, using either light (L) or buzzer noise (N) as the "go" signal, a compound "no go" signal (NL in the L-"go" groups and LN in the N-"go" groups), and either an extinction or a passive avoidance contingency during the "no go" signal (4 weeks of training, starting at 60 days).(ABSTRACT TRUNCATED AT 250 WORDS)
Amphetamine↗
Development of mouse activity, stimulus reactivity, habituation, and response to amphetamine and scopolamine.
Twenty-four litters of non-inbred Swiss-derived mice were used to study the development of locomotion and tendency to approach a novel object in an open field, as well as the effects of dl-amphetamine sulfate and scopolamine hydrochloride (1 or 2 mg/kg IP). Brief (7 min) tests repeated for three consecutive days were preferred in order to obtain information on between-session habituation. Animals tested on days 14-16 showed low levels of activity without changes in successive sessions. In contrast, an adult-like pattern with a high initial activity and marked between-session decrements prevailed on days 21-23 and 28-30. Dl-amphetamine elevated activity only on days 14-16, while scopolamine produced hyperactivity and impaired habituation only on days 21-23 and 28-30. Latency to approach a novel object by untreated animals showed a substantial reduction between the end of the second week and subsequent developmental stages. This went hand in hand with an appearance of latency increases after dl-amphetamine treatments, while an opposite trend in the scopolamine data failed to reach statistical significance. Activity tests in a photocell apparatus at 61-72 days (without prior treatment) showed a reduction of locomotion relative to the level measured in animals from other litters raised in parallel and not subjected to early testing. Overall, the present data and those of the literature indicate that some developmental phenomena in small rodents are relatively insensitive to a variety of organismic, environmental, and test factors, while others (e.g., inverted U-shaped activity trends and successive modifications of the amphetamine profile) depend on complex interactions between several variables.
Age Factors↗
Behaviorally augmented versus other components in organophosphate tolerance: the role of reinforcement and response factors.
Male Wistar-derived rats were used to assess the behaviorally augmented component of tolerance to paraoxon depression of a feeding response. Separate groups of animals were treated daily by 0.125 mg/kg of the compound given sc either 1 hr before the start or 45 min after the end of a 90-min feeding session. However, the dose was reduced to 0.0625 mg/kg from Day 9 to Day 12 of the treatment series if animals showed too severe a reduction in food consumption. After development of tolerance by the presession treatment group, the animals treated after feeding were shifted to treatment before feeding. This shift produced a marked depression in food consumption. This confirms similar data previously obtained by a different test (two-way avoidance), and indicates that behaviorally augmented tolerance to paraoxon related to practice factors may be a fairly general phenomenon. Other experiments were to assess the effects of paraoxon in the conditioned taste aversion (CTA) paradigm. These showed the development of an aversion only at high dosage levels (two pairings between the flavor cue and 0.25 mg/kg sc, or four pairings with a 0.17-mg/kg dose). However, the failure of lower doses to produce CTA may have depended on the relatively slow onset of the intoxication, producing an extended interval between the end of cue exposure and the development of malaise or illness. Two pretreatments given 6 and 3 days before the first conditioning session in an experiment using the 2 X 0.25-mg/kg schedule did not affect the development of CTA as measured by a conventional double-bottle test. However, a typical interference effect produced by prior exposure was shown by a substantial acceleration of subsequent CTA extinction in pretreated animals.
Animals↗
Comparative in vitro cytotoxicity of cyclophosphamide, its major active metabolites and the new oxazaphosphorine ASTA Z 7557 (INN mafosfamide).
Cyclophosphamide (CPA), the most commonly used alkylating agent in the treatment of a wide variety of hematologic and solid tumors, requires oxidation by hepatic microsomal enzymes to its active alkylating species. A number of alternative methods exist to simulate the in vitro cytotoxicity of CPA against animal and human tumors, including the co-incubation of CPA with the S-9 fraction of rat liver homogenates (S-9) and the use of either 4-hydroperoxy CPA (a stabilized form of a major blood-borne metabolite of CPA), phosphoramide mustard (PM, considered to be the ultimate intracellular alkylating metabolite of CPA), or ASTA Z 7557 [4-(2-sulfonatoethylthio)-CPA, a new oxazaphosphorine compound which after dissolution undergoes rapid spontaneous hydrolysis in vitro with liberation of 4-hydroxy-CPA]. Using a human tumor clonogenic assay (HTCA) we have quantitated the median molar inhibitory dose 50 (ID50) concentrations of S-9 activated-CPA, 4-hydroperoxy-CPA, PM, and ASTA Z 7557 against 107 previously untreated tumors, as well as determining the in vitro biological stability of the former three CPA metabolite preparations. 4-Hydroperoxy-CPA proved the most consistently cytotoxic (median molar ID50 = 5.7 X 10(-5)M) compound, followed by ASTA Z 7557, S-9 activated-CPA and PM in that order. Of additional interest S-9 activated CPA and PM proved relatively unstable biologically when frozen at -120 degrees C, whereas 4-hydroperoxy-CPA lost none of its cytotoxicity over a 36 day period during freezing.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Scopolamine and acquisition of go-no go avoidance: a further analysis of the perseverative antimuscarinic deficit.
Rats treated with scopolamine (0.5 mg/kg SC daily) during the acquisition of a discrimination task with symmetrical negative reinforcement (light-go, noise/light-no go) showed a learning impairment, with both active and passive avoidance deficits. In the initial stage of such training, however, fewer passive avoidance errors and more active avoidance errors were made by treated animals if active avoidance pretraining had occurred in the no-drug state. A similar experiment using the same stimulus arrangement with asymmetrical reinforcement (no punishment of intertrial, and no go signal, responses) showed a scopolamine effect consisting mainly of increased responding to extinction signals and during intertrial intervals, with little or no active avoidance deficit. Furthermore, interactions due to changes in treatment conditions in successive stages of training were minimized in the latter task, suggesting that the effects of the shift-no shift factor on distribution of errors in the early stages of active-passive avoidance learning were unlikely to have been due to a genuine drug dissociation. Overall, these results and others obtained previously in the same and related tasks tend to rule out some unidimensional explanations of antimuscarinic effects, e.g., response disinhibition (an exclusively motor deficit) or impairment of stimulus sensitivity (an exclusively sensory deficit). The data rather confirm the notion of a sensorimotor drug bias leading to a shift in response prepotencies depending jointly on stimuli, responses, and response consequences. Prior learning history and behavioural compensation for adverse treatment consequences at the reinforcement level may interact with the sensorimotor bias so as to produce "set perseveration" (perseveration of response tendencies).
Animals↗
Amphetamine, conditioned stimulus, and nondebilitating preshock effects on activity and avoidance: further evidence for interactions between associative and nonassociative changes.
A literature survey and preliminary experiments with rats on the consequences of shock preexposure on subsequent activity and escape or avoidance showed the need for further work on the interactions between nondebilitating preshock and various test and treatment factors. The two main experiments used 16 preexposure conditions, namely, presence or absence of unavoidable punishment (36 shocks of 2.5 mA and 5 sec subdivided in three daily sessions), a light CS, a central partition in the shuttle-box, and dl-amphetamine sulfate (1 mg/kg ip 15 min before each session). In both experiments the four factors studied exerted more than additive effects on activity in preexposure sessions, leading to a very high frequency of crossing in the CS-shock-no-partition-drug condition. Upon retesting for activity (Experiment 1) suppression of locomotion by prior shock was less marked in animals preexposed to CS-US pairings in the absence of partition, while proactive amphetamine effects consisted mainly of a progressive increase of activity over successive retest sessions in the groups not preshocked. Upon retesting for light-cued, two-way avoidance acquisition (Experiment 2) the groups preexposed to US only were mostly retarded, while those preexposed to paired CS and US were mostly facilitated. Other changes, including drug pretreatment consequences, were negligible or unsystematic, but in general the data showed that the effects of various preexposure conditions on activity could not account for those on avoidance. Overall, it appears that the interactions between nondebilitating preshock and other test and treatment factors can be further exploited to clarify the respective roles of various associative and nonassociative mechanisms in modulation of activity and adaptive responding in aversive situations.
Amphetamine↗
Test factors affecting the time course of avoidance depression after DFP and paraoxon.
The time course of avoidance depression induced by DFP and Paraoxon in rats was measured in four experiments using sublethal doses which induced approximately equivalent changes at the time for maximal behavioral depression (3 hr after 1.1 mg/kg DPF or 0.25 mg/kg Paraoxon SC). The trends obtained with pretrained animals intoxicated for the first time, and not tested during the period between treatment and testing at any given interval (3, 8, 13, 18, and 24 hr after injection), served as baselines to assess (1) proactive consequences of one or more avoidance sessions on subsequent measurements, and (2) sensitivity changes upon repetition of treatment with the same or the other agent after a 5-week resting period. The changes in the time course of avoidance depression due to these factors were generally unimpressive. Some of the interactions observe, however, provided direct or indirect evidence (1) for an enhanced residual depression at long post-treatment intervals upon repetition of organophosphate intoxication; (2) for a proactive impairing effect sometimes appearing after behavioral testing at the time of maximal depression (3 hr), when total or near-total avoidance failure causes extensive exposure to shock; and (3) for a proactive facilitating effect sometimes appearing after testing at a time of moderate avoidance impairment (8 hr), which may be ascribed to behaviorally augmented tolerance ("learned" tolerance).
Animals↗
Methodological problems in the analysis of behavioral tolerance in toxicology.
The analysis of selected data on differential behavioral tolerance to drugs and other chemicals leads to a series of tentative methodological proposals with potential interest for the purposes of toxicology. These data show a wide range of different relations between tolerance induced by continued exposure to treatment per se and tolerance dependent on specific treatment-behavior interactions, such as behavioral testing in the treatment state and unfavorable consequences on reinforcement density of response changes induced by treatment. Consequently, when tolerance phenomena occurring with a particular type of treatment deserve an in-depth analysis, a sequential strategy should assess (i) critical factors in short-term compensation for behavioral deficits (acute behaviorally augmented tolerance), (ii) relations between sensitization and tolerance phenomena (particularly in the case of agents with long-lasting and/or cumulative physiological-biochemical effects), with special regard to tolerance development in the absence of measurable changes in the lower dosage ranges, and (iii) factors responsible for behaviorally augmented tolerance in medium-and long-term experiments. The latter analysis may require the investigation of different relations between time of treatment and time of testing, and different treatment-induced changes in reinforcement density. Specific and non-specific transfer of coping responses across situations must also be considered, as well as changes in response topographies, interindividual differences in rate of tolerance development as a function of size and direction of the original treatment changes, and several other cues which can facilitate the understanding of the phenomena observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacological evidence on the specialization of CNS mechanisms responsible for motor act inhibition by aversive events.
Our use of selected pharmacological agents has now extended the range of treatment-behaviour interactions previously studied by other (e.g., lesion) approaches in the search for appropriate models of behaviour organization and underlying physiological mechanisms. The case of muscarinic blockers has special interest, because the drugs induce only one type of primary change. At present, it appears difficult to reconcile the evidence in favour of a motor (perseverative) deficit with other evidence favouring an impairment of sensory processes. However, critical experiments using several go-no go avoidance tasks show that the two deficits may be inseparable. The complex profile of cue-dependent disinhibitory effects of antimuscarinics suggests that separate sensori-motor mechanisms are employed for response suppression not simply as a function of cue type, response type, or response-reinforcement relation but as a joint function of all these factors. Sedative-tranquillizing agents with so-called anti-conflict properties add still another dimension to the problem of motor act inhibition. These agents are maximally effective in disrupting response withholding when both reward and punishment follow the emission of a particular response, less consistently effective in tests with CS paired with non-contingent shock (CER), and mostly ineffective in those go-no go avoidance tasks which show a very high sensitivity to muscarinic blockade.
Animals↗
A pharmacological analysis of processes underlying differential responding: a review and further experiments with scopolamine, amphetamine, lysergic acid diethylamide (LSD-25), chlordiazepoxide, physostigmine, and chlorpromazine.
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Amphetamine↗